Project Summary Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive disease with no known cure and no treatment that convincingly alters the disease course or significantly improves mortality. The objective of this proposal is the development of nebulized delivery of the small molecule inhibitor of Wnt/?-catenin signaling, BC-2059, for Idiopathic Pulmonary Fibrosis. Pre-clinical studies in rodents, dogs, and minipigs show that BC-2059 has favorable pharmacokinetics and safety data with intravenous administration, which provides support for short-term use. However, in a chronic disease, such as IPF, which requires prolonged treatment, intravenous administration is undesirable for patients. Nebulization of BC-2059 would achieve high local levels of the drug, while minimizing off-target side effects in other critical organs, which is key for the chronic treatment of patients with pulmonary fibrosis. In Specific Aim 1, a respiratory formulation of BC-2059 will be optimized to generate particle sizes ?3 ?m to allow for maximal distribution into the alveolar spaces. In Specific Aim 2, the efficacy and pharmacodynamics of nebulized administration of BC-2059 will be determined in vivo using two mouse models of chronic pulmonary fibrosis, using intratracheally administered asbestos and repetitive intratracheal administration of bleomycin, both of which create non-resolving fibrosis. Nebulized BC-2059 will be administered after the establishment of pulmonary fibrosis, in order to determine whether the drug improves the resolution of fibrosis, which would increase its translational potential and make a clinically meaningful impact for patients. The overall goal for this Phase 1 application is the generation of high quality pre-clinical data that will provide a highly compelling rationale for clinical trials for the treatment of IPF and potentially other fibrotic lung diseases.